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Epithelial-mesenchymal transition-associated secretory phenotype predicts survival in lung cancer patients.

ABSTRACT: In cancer cells, the process of epithelial-mesenchymal transition (EMT) confers migratory and invasive capacity, resistance to apoptosis, drug resistance, evasion of host immune surveillance and tumor stem cell traits. Cells undergoing EMT may represent tumor cells with metastatic potential. Characterizing the EMT secretome may identify biomarkers to monitor EMT in tumor progression and provide a prognostic signature to predict patient survival. Utilizing a transforming growth factor-?-induced cell culture model of EMT, we quantitatively profiled differentially secreted proteins, by GeLC-tandem mass spectrometry. Integrating with the corresponding transcriptome, we derived an EMT-associated secretory phenotype (EASP) comprising of proteins that were differentially upregulated both at protein and mRNA levels. Four independent primary tumor-derived gene expression data sets of lung cancers were used for survival analysis by the random survival forests (RSF) method. Analysis of 97-gene EASP expression in human lung adenocarcinoma tumors revealed strong positive correlations with lymph node metastasis, advanced tumor stage and histological grade. RSF analysis built on a training set (n = 442), including age, sex and stage as variables, stratified three independent lung cancer data sets into low-, medium- and high-risk groups with significant differences in overall survival. We further refined EASP to a 20 gene signature (rEASP) based on variable importance scores from RSF analysis. Similar to EASP, rEASP predicted survival of both adenocarcinoma and squamous carcinoma patients. More importantly, it predicted survival in the early-stage cancers. These results demonstrate that integrative analysis of the critical biological process of EMT provides mechanism-based and clinically relevant biomarkers with significant prognostic value.

SUBMITTER: Reka AK

PROVIDER: S-EPMC4043235 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Epithelial-mesenchymal transition-associated secretory phenotype predicts survival in lung cancer patients.

Reka Ajaya Kumar AK Chen Guoan G Jones Richard C RC Amunugama Ravi R Kim Sinae S Karnovsky Alla A Standiford Theodore J TJ Beer David G DG Omenn Gilbert S GS Keshamouni Venkateshwar G VG

Carcinogenesis 20140207 6

In cancer cells, the process of epithelial-mesenchymal transition (EMT) confers migratory and invasive capacity, resistance to apoptosis, drug resistance, evasion of host immune surveillance and tumor stem cell traits. Cells undergoing EMT may represent tumor cells with metastatic potential. Characterizing the EMT secretome may identify biomarkers to monitor EMT in tumor progression and provide a prognostic signature to predict patient survival. Utilizing a transforming growth factor-β-induced c ...[more]

PMID: 24510113

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Project description:Background: Epithelial-mesenchymal transition (EMT) plays an important role in the invasion and migration during cancer metastasis. Wnt3a is one of the ligands in canonical Wnt/β-catenin signaling pathway, which contributes to the carcinogenesis and progression of lung cancer cell lines. The aim of this study was to evaluate the association between Wnt3a and EMT-related proteins (E-cadherin and N-cadherin), and to further investigate its impact on prognosis of lung adenocarcinoma patients. Methods: A total of 147 lung adenocarcinoma patients were included and their clinicopathological characteristics were collected in this retrospective study. The expression levels of Wnt3a, E-cadherin and N-cadherin in post-surgery cancerous and adjacent normal tissues were assessed by immunohistochemistry. The association between Wnt3a and EMT-related proteins and their prognostic values were systematically evaluated. HCC827 and PC9 cell lines were treated with Wnt3a to detect the expression of EMT-related and Wnt/β-catenin signaling-associated proteins, as well as the in vitro migration and invasion abilities. Results: High Wnt3a expression level was significantly associated with low E-cadherin (P<0.001) and high N-cadherin (P<0.001) expression levels in lung adenocarcinoma tissues. Besides, high Wnt3a level predicted poorer lung adenocarcinoma survival by univariate Cox analysis (P=0.001), while the multivariate result was not significant (P=0.355). Subgroup analysis suggested that the prognostic value of Wnt3a expression level was significant in stage T1-T2 (log rank P=0.003) and stage N0 (log rank P=0.031) patients. The multivariate Cox analysis suggested N-cadherin was an independent prognostic factor for lung adenocarcinoma patients (P=0.012). After including these markers into a nomogram, the Harrell's C-index of the nomogram was 0.755. The decision-curve analysis of our nomogram performed net benefit at the threshold probability from 21.6% to 82.0%, and the current model had a better prognostic value than TNM-classification with a lower Akaike information criterion (AIC) value of 166.54. In vitro experiments suggested that Wnt3a could regulate EMT-related proteins and promotes in vitro invasion and migration abilities. Conclusions: Wnt3a could regulate EMT-related proteins and promote the migration and invasion process of lung adenocarcinoma. Although its value as an independent prognostic factor was limited, the combined model suggested good prognostic performance for lung adenocarcinoma patients.

Dataset Information

Epithelial-mesenchymal transition-associated secretory phenotype predicts survival in lung cancer patients.

Publications

Epithelial-mesenchymal transition-associated secretory phenotype predicts survival in lung cancer patients.

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